Process for the synthesis of (s) 3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid

Abstract

Provided herein are processes, compounds and compositions for making (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid. Also provided herein a pharmaceutical compositions containing (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid.

What is claimed is: 
     
       1. A pharmaceutical composition comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (1), or a pharmaceutically acceptable salt thereof, and one or more of the following compounds: (1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one (2), (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one (3), (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]heptan-6-yl acetate (4), (1R,4R,6S,7R)-7-bromo-6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (25), (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5), (1R,4R,7R)-7-bromo-6-(difluoromethylene)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6), (1R,4R,7R)-7-bromo-6-(difluoromethylene)-2-azabicyclo[2.2.1]heptan-3-one (7), (1R,4R,7R)-7-bromo-6-(difluoromethylene)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8), methyl (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylene)cyclopent-1-ene-1-carboxylate (9), ethyl (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylene)cyclopent-1-ene-1-carboxylate (15), and (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylene)cyclopent-1-ene-1-carboxylic acid (19), or a pharmaceutically acceptable salt of any of the preceding compounds. 
     
     
       2. The pharmaceutical composition of  claim 1  comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (1), or a pharmaceutically acceptable B salt thereof, and from 0.0001 to 1 mg of (1R,4S)-2-azabicyclo[2.2.1]hept-5-en-3-one (2), or a pharmaceutically acceptable salt thereof. 
     
     
       3. The pharmaceutical composition of  claim 1  comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (1), or a pharmaceutically acceptable salt thereof, and from 0.0001 to 1 mg of (1R,4S)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]hept-5-en-3-one (3), or a pharmaceutically acceptable salt thereof. 
     
     
       4. The pharmaceutical composition of  claim 1  comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (1), or a pharmaceutically acceptable B salt thereof, and from 0.0001 to 1 mg of (1R,4R,6S,7R)-7-bromo-2-(4-methoxybenzyl)-3-oxo-2-azabicyclo[2.2.1]heptan-6-yl acetate (4), or a pharmaceutically acceptable salt thereof. 
     
     
       5. The pharmaceutical composition of  claim 1  comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (1), or a pharmaceutically acceptable B salt thereof, and from 0.0001 to 1 mg of (1R,4R,7R)-7-bromo-6-hydroxy-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (25), or a pharmaceutically acceptable salt thereof. 
     
     
       6. The pharmaceutical composition of  claim 1  comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (1), or a pharmaceutically acceptable B salt thereof, and from 0.0001 to 1 mg of (1R,4R,7R)-7-bromo-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptane-3,6-dione (5), or a pharmaceutically acceptable salt thereof. 
     
     
       7. The pharmaceutical composition of  claim 1  comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (1), or a pharmaceutically acceptable B salt thereof, and from 0.0001 to 1 mg of (1R,4R,7R)-7-bromo-6-(difluoromethylene)-2-(4-methoxybenzyl)-2-azabicyclo[2.2.1]heptan-3-one (6), or a pharmaceutically acceptable salt thereof. 
     
     
       8. The pharmaceutical composition of  claim 1  comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (1), or a pharmaceutically acceptable salt thereof, and from 0.0001 to 1 mg of (1R,4R,7R)-7-bromo-6-(difluoromethylene)-2-azabicyclo[2.2.1]heptan-3-one (7), or a pharmaceutically acceptable salt thereof. 
     
     
       9. The pharmaceutical composition of  claim 1  comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (1), or a pharmaceutically acceptable salt thereof, and from 0.0001 to 1 mg of (1R,4R,7R)-7-bromo-6-(difluoromethylene)-2-(tert-butoxycarbonyl)-2-azabicyclo[2.2.1]heptan-3-one (8), or a pharmaceutically acceptable salt thereof. 
     
     
       10. The pharmaceutical composition of  claim 1  comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (1), or a pharmaceutically acceptable salt thereof, and from 0.0001 to 1 mg methyl of (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylene)cyclopent-1-ene-1-carboxylate (9), or a pharmaceutically acceptable salt thereof. 
     
     
       11. The pharmaceutical composition of  claim 1  comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (1), or a pharmaceutically acceptable B salt thereof, and from 0.0001 to 1 mg of ethyl (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylene)cyclopent-1-ene-1-carboxylate (15), or a pharmaceutically acceptable salt thereof. 
     
     
       12. The pharmaceutical composition of  claim 1  comprising (S)-3-amino-4-(difluoromethylenyl)cyclopent-1-ene-1-carboxylic acid (1), or a pharmaceutically acceptable salt thereof, and from 0.0001 to 1 mg of (S)-3-((tert-butoxycarbonyl)amino)-4-(difluoromethylene )cyclopent-1-ene-1-carboxylic acid (19), or a pharmaceutically acceptable salt thereof.